tbuckley/cabot-search huggingface dataset:
Germline DNA damage response (DDR) mutations in an East Asian (EA) cohort with prostate cancer (PCa).
Authors: Joanne Y.H. Lua, Johan W.K. Chan, Enya H.W. Ong, Melody Chow, Kae-Jack Tay, Jeffrey K.L. Tuan, Michael L.C. Wang, Lui Shiong Lee, Ravindran Kanesvaran, Li Yan Khor, Melvin L.K. Lee Kiang Chua
Journal: Journal of Clinical Oncology (2023)

373 Background: Aberrations of the DDR pathway have been shown to be prognostic of survival and predictive of PARP inhibition in PCa. Additionally, germline mutations in DDR genes are linked to PCa susceptibility. Here, we report the germline DDR mutation frequencies in an EA PCa cohort, and their associations with clinicopathological indices and outcomes. Methods: We utilized a prospectively recruited cohort of 891 EA patients, with centrally assessed Gleason’s score (GS) by an expert pathologist. Germline mutation profiling was performed by whole exome sequencing (100X) using the Illumina Novaseq (CA). Following joint genotyping, common variants of ≥1% were filtered, and only variants defined as pathogenic (P)/likely pathogenic (LP) in ClinVar or predicted to be P by CADD or REVEL were retained. We used a 32 DDR gene-set for tests of association with clinicopathological indices, biochemical relapse-free rate (bRFR), and distant metastasis-free survival (DMFS). Results: Median follow up was 54 (33-83) mo; median age at diagnosis was 70 (64-74) y. 741 (84%) men had localized PCa, 65 (7%) had N+M0, and 80 (9%) had M1 disease. Among those with localized PCa, 417 (56%) were stratified as NCCN high/very high. 5-year DMFS was 100%, 96%, 86%, and 74% for NCCN low, intermediate, high/very high, and N+M0 PCa, respectively. 31 (3.5%) men in our cohort harbored a P/LP variant in at least one of the 32 DDR genes; P/LP variants were most frequently observed for BRCA2 (N=11[1.2%]), ATM (N=6[0.7%]), and RAD50 (N=5[0.6%]). P/LP variants were more frequent in men with N+M0/M1 compared with those with localized PCa (29% vs 16%, P=0.05), and in men with GS 9-10 vs 6-8 tumors (43% vs 20%, P=0.002). Presence of P/LP DDR variants were significantly associated with bRFR (HR 2.44 [95% CI:1.0-6.1], P=0.049) in M0 patients treated with RT+/-hormonal therapy on univariable and multivariable analyses. Conclusions: Herein, we observed lower frequencies of germline DDR P/LP mutations in our EA PCa cohort than other published Chinese cohorts (Wei, et al. 2018; Wei, et al. 2020). Nonetheless, there was a strong trend for increased incidence of DDR mutations with more advanced PCa. Men with DDR mutations were more likely to fail treatment than men without. [Table: see text]
Efficacy and safety of docetaxel (D) vs androgen-receptor signaling inhibitors (ARSi) as second-line therapy (Rx) after progression on alternative ARSi as first-line Rx for patients who are elderly (≥75 years old) with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter international database: A SPARTACUSS–Meet-URO 26 study.
Authors: Vincenzo Gennusa, Calogero Saieva, Richard M. Lee-Ying, Pier Vitale Nuzzo, Gian Paolo Spinelli, Elisa Zanardi, Giuseppe Fotia, Sabrina Rossetti, Loana Bueno Valenca, Anna Patrikidou, Livia Andrade, Ricardo Pereira Mestre, Giuseppe Fornarini, Giuseppe Procopio, Daniele Santini, Christopher Sweeney, Daniel Yick Chin Heng, Ugo De Giorgi, Antonio Russo, Edoardo Francini
Journal: Journal of Clinical Oncology (2023)

166 Background: About 2/3 of all prostate cancer (PCa) deaths occur in patients aged ≥75, who are frequently diagnosed with advanced PCa. ARSi abiraterone acetate (AA) and enzalutamide (E) are the most common 1 st line Rx for patients with mCRPC. Yet, the optimal treatment sequence for the elderly ≥75 after ARSi failure is still unclear. Methods: Using available medical records, patients aged ≥75 who started ARSi as 1 st line Rx for mCRPC within January 2015 - April 2019 and, upon progression, 2 nd line alternative ARSi or D were identified from the IRB approved hospital registries of 10 centers in Europe, North and South America. Patients were categorized by type of 2 nd line Rx for mCRPC into cohorts AA/E and D. Primary endpoints were overall survival (OS) from 1 st line AA/E start, OS and radiographic progression-free survival (rPFS) from 2 nd line Rx start, and safety. The Kaplan Meier method was used to calculate endpoint distributions and medians (95% CI). Results: Of the 122 patients identified, 57 (46.7%) had AA/E and 65 (53.3%) D, as 2 nd line Rx for mCRPC. Median follow-up was 26.3 months (95% CI, 23.1-27.9 months). Cohort AA/E tended to be older (81 vs 78 years; p=0.001) and with high-volume disease (45.5% vs 25.0%; p=0.022) compared to cohort D. No significant difference in OS from 1 st line ARSi onset and OS or rPFS from 2 nd line Rx start was found between the 2 cohorts. Cohort AA/E had longer rPFS than cohort D, albeit not significant (18.5 vs 12.0 months; p=0.13). Rates of adverse events (AEs) of any grade (42.1 vs 53.8; p=0.21) and AEs of grade ≥3 (19.3% vs 18.5%; p=1.0) did not show significant differences between the 2 cohorts. Conclusions: Within the limitations of small cohorts and retrospective design, treatment sequences with 2 nd line AA/E or D after failure of 1 st line alternative ARSi for mCRPC showed similar efficacy and safety in the elderly ≥75 years old.
Effect of early PSA decline after starting second-generation hormone therapy in the post-docetaxel setting on cancer-specific survival in metastatic castrate-resistant prostate cancer.
Authors: Kelly Lehner, Mohamed E. Ahmed, Raevti Bole, Jack R. Andrews, Rimki Haloi, Michael S. Bold, Ayse T. Kendi, R. Jeffrey Karnes, Eugene D. Kwon, Alan Haruo Bryce
Journal: Journal of Clinical Oncology (2023)

189 Background: The objective of this study is to evaluate the prognostic value of early PSA decline following initiation of second-generation hormone therapy (2 nd HT), namely abiraterone acetate or enzalutamide, in the post-chemotherapy setting in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods: We retrospectively identified 75 m-CRPC patients treated with 2 nd HT following docetaxel failure (defined as PSA rise and radiographic progression). Patients were categorized into two groups based on first PSA within 3 months after initiation of therapy: PSA reduction ≥ 50% (Group A) and PSA reduction &lt; 50% (Group B). The primary endpoint was cancer-specific mortality and the secondary endpoint was radiographic progression free survival. Results: There were 75 patients (52 in group A, 23 in group B) in the analytic cohort. Baseline clinical and demographic characteristics, including median age, primary Gleason score risk group, median pre-treatment PSA, disease burden, site of metastases, and pre-treatment ECOG score were not statistically different between the two groups. PSA reduction ≥50% was significantly associated with decreased risk of radiographic disease progression (HR 0.41, 95%CI 0.21-0.80, p = 0.0113) as well as decreased risk of cancer-specific mortality (HR 0.29, 95%CI 0.09-0.87, p = 0.0325). Conclusions: PSA reduction ≥50% within 3 months of starting 2 nd HT for patients with mCRPC who have failed first-line docetaxel is associated with significantly improved 3-year cancer-specific mortality and progression free survival. Our data supports the use of PSA as an early prognosticating marker for patient outcomes on this second line therapy. [Table: see text]
P3BEP (ANZUP 1302): An international randomized phase 3 trial of accelerated versus standard BEP chemotherapy for male and female adults and children with intermediate- and poor-risk metastatic germ cell tumours (GCTs).
Authors: Danka Zebic, Martin R. Stockler, Andrew James Martin, Farzana D. Pashankar, Ben Tran, Danish Mazhar, Robert A Huddart, Matthew Wheater, Euan Thomas Walpole, Elaine Dunwoodie, Darren R. Feldman, Alison Jane Birtle, Amanda Gwendolyn Stevanovic, David Wyld, Fritha J. Hanning, Peter S. Grimison
Journal: Journal of Clinical Oncology (2023)

TPS431 Background: Bleomycin, etoposide, and cisplatin (BEP) given 3-weekly x 4 remains standard 1st line chemotherapy for intermediate or poor risk metastatic GCT. Accelerating standard regimens by shortening the cycle length to 2-weekly improved cure rates in other cancers. P3BEP will determine effects of accelerated versus standard BEP in this setting. This is a first international, randomized trial of chemotherapy for intermediate and poor-risk metastatic GCT to include adults and children of both sexes. Methods: This open label, randomized, phase 3 trial is conducted seamlessly in 2-stages. The primary endpoint for stage I (n=150) was complete response (CR); and for stage 2 (n=500) is progression free survival at 2 years (PFS2y). These sample sizes provide &gt;80% power with a two-sided type I error rate of 5% to detect an absolute improvement of 25% in the CR rate (stage 1) and of 7% in the PFS2y (stage 2). The target population is males and females aged 11 to 45 with intermediate-or poor-risk metastatic GCT of the testis, ovary, retroperitoneum, or mediastinum. Participants are randomized (1:1) to 4 cycles of standard BEP (q3w) or accelerated-BEP (q2w) with cisplatin 20mg/m 2 D1-5, etoposide 100mg/m 2 D1-5, bleomycin 30 KIU weekly x 12, and pegylated G-CSF D6 or filgrastim daily. Study assessments occur at 30 days after completing chemotherapy, 6 months from randomization, and after completion of all post-chemotherapy treatments (e.g. surgery). Tumour and baseline blood samples are collected for translational substudies. Progress: As of Sept 2022, 226 participants have been recruited from 24 ANZ sites, 17 UK sites (led by Cambridge Clinical Trials Unit), and 149 USA sites (led by Children’s Oncology Group). The first planned interim analysis for safety (n=76) identified no safety concerns. Stage I analysis (n=150) showed sufficiently favorable results with no futility concerns, supporting ongoing trial recruitment. Clinical trial information: NCT02582697 .
Randomised phase II trial of adaptive image guided radiotherapy in muscle invasive bladder cancer: Late toxicity and cancer outcomes.
Authors: Robert A Huddart, Shaista Hafeez, Abdullahi Omar, Alison Jane Birtle, Ka Ching Cheung, Ananya Choudhury, Farshad Foroudi, Hannah Gribble, Clare Griffin, Ann Henry, Ben Hindson, Rebecca Lewis, Duncan McLaren, Helen McNair, Ashok Nikapota, Omi Parikh, Isabel Syndikus, Mohini Anna Varughese, Amanda Webster, Emma Hall
Journal: Journal of Clinical Oncology (2023)

446 Background: The bladder is a mobile, deformable structure which makes radiotherapy (RT) delivery challenging. Plan of the day (POD) adaptive image guided RT and tumour boost dose escalation can optimise treatment. We aimed to define a feasible, safe schedule for muscle invasive bladder cancer (BC) using these techniques. Methods: RAIDER (ISRCTN 26779187) is a 3-arm, international phase II trial. Participants (pts) had unifocal T2-T4a urothelial BC and were randomized (1:1:2) to: standard whole bladder RT (WBRT), standard dose adaptive tumour focused RT (SART) or dose escalated adaptive tumour boost RT (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 64Gy/32f or 55Gy/20f and DART was 70Gy/32f or 60Gy/20f. For SART and DART, POD (small, medium, large) was chosen daily. Neoadjuvant chemotherapy (NAC) and concomitant radiosensitising therapy (CTh) were permitted. Primary endpoint is proportion of pts with RT related CTCAE grade≥3 (G≥3) toxicity 6-18 months (m) after RT. A non-comparative design to rule out &gt;20% G≥3 toxicity in DART pts required 57 evaluable DART pts in each fractionation cohort (90% power, 5% 1-sided alpha). Adverse events (AE) are treatment emergent with RT relatedness assessed blind to treatment allocation. In each fractionation cohort, toxicity analysis is by treatment received in the evaluable population (pts with at ≥1 toxicity assessment between 6-18m). 3m local control was assessed by cystoscopic biopsy. Cancer outcomes are analysed by intention-to-treat with fractionation cohorts combined. Results: 345 pts were randomised (Oct 2015 - Apr 2020): 46/41 WBRT, 46/41 SART and 90/81 DART pts in 32f/20f cohorts respectively. Baseline characteristics for 32f/20f were median age 73 years (IQR 67, 79)/ 72 (67, 79); 83%/ 78% T2; 46%/ 52% had NAC and 71%/ 70% CTh. Median follow-up was 32f: 38.2m (IQR 26.2, 50.2), 20f: 42.1m (35.6, 50.1). 3588/6222 (58%) fractions delivered to SART and DART pts used small or large POD. Late toxicity outcomes are shown in table. RT related G≥3 in 20f DART was 1/58 (90% CI 0.1, 7.9) and in 32f DART was 0/57. 3m local control was achieved in 44/51 (86%) WBRT, 45/53 (85%) SART and 82/92(89%) DART. 2 year survival was 79% (95% CI: 69, 86) WBRT, 74% (63, 82) SART and 80% (73, 85) DART. Conclusions: Late G≥3 toxicity was low in all treatment groups. 20f and 32f DART was safe and feasible to deliver with toxicity rates below predefined thresholds. Local control for image guided (chemo)RT was good. CTCAE G≥3 and G≥2 treatment emergent toxicity 6-18m after RT. Clinical trial information: 26779187 . [Table: see text]
Extreme bipolar androgen therapy with darolutamide and testosterone cypionate in patients with metastatic castration-resistant prostate cancer: ExBAT (LACOG 0620) trial.
Authors: Pedro H Isaacsson Velho, Daniel da Motta Girardi, Andrey Soares, Denis Leonardo Fontes Jardim, Fernando Cotait Maluf, Igor Alexandre Morbeck, Mariane Fontes Dias, Vinicius Carrera Souza, Adriano Goncalves E Silva, Rafaela Gomes de Jesus, Taiane Francieli Rebelatto, Diogo Assed Bastos
Journal: Journal of Clinical Oncology (2023)

TPS276 Background: Prostate cancer has an intrinsic dependence on androgens and androgen receptor (AR) regulation. Suppression of gonadal androgen synthesis known as androgen deprivation therapy (ADT), either by orchiectomy or by pharmacological modulation, represents the treatment backbone of metastatic disease. Unfortunately, almost invariably, patients develop resistance to ADT, progressing to a state called castration-resistant prostate cancer (CRPC), defined as disease progression at serum testosterone levels in the castrate range. Bipolar Androgen Therapy (BAT), consisting of exogenous supraphysiological doses of testosterone followed by castrate levels, has shown clinical activity in multiple early phase clinical trials, in addition to improvement of quality of life (QoL) in CRPC patients. Alternated administration of BAT and novel AR-targeted therapies, a strategy entitled by our group as Extreme Bipolar Androgen Therapy (ExBAT), has never been tested in patients with CRPC. The objective of our study is to assess the ExBAT approach in metastatic CRPC. Methods: ExBAT (NCT04558866) is a phase 2, single-arm, multicenter trial assessing patients with mCRPC who progressed to abiraterone by PCWG3 criteria. Prior docetaxel for metastatic hormone-sensitive disease is allowed if ≥ 12 months elapsed from last dose of docetaxel. Included patients receive testosterone cypionate 400 mg IM on day 1 followed by darolutamide 1,200 mg/day orally for 4 weeks (starting on day 29 through day 56) on 63-day cycles. The primary endpoint is radiographic progression-free survival (rPFS) at 12 months. Secondary endpoints include PSA decline rates, overall survival, toxicity, quality of life, and predictive biomarkers of response/survival. Tumor assessments are performed every 9 weeks, for the first 2 cycles and every 18 weeks thereafter up to 12 months. Patients with disease progression with clinical benefit are allowed to continue treatment. Patients without disease progression after 12 months are allowed to receive study treatment on Extension Phase. The sample size of 47 patients (considering 5% drop-out) was calculated based on the primary endpoint using a two-sided 5% significance level Chi-square Test for One Proportion and achieves 80% power to detect the difference between a 50% rPFS at 12 months comparing with 30% in the historic control group. NCT04558866. From June2021 to September2022, 31 of planned 47 patients have been enrolled in 8 Brazilian centers. Results are not available at the time of submission. Clinical trial information: NCT04558866 .
Deep prostate-specific antigen response and overall survival in patients with metastatic castration-sensitive prostate cancer: A systematic review and meta-analysis.
Authors: Syed Arsalan Ahmed Naqvi, Irbaz Bin Riaz, Manal Imran, Muhammad Daim Bin Zafar, Kunwer Sufyan Faisal, Zaryab Bin Riaz, Parminder Singh, Alan Haruo Bryce
Journal: Journal of Clinical Oncology (2023)

195 Background: Preliminary data suggests that patients with metastatic castration-sensitive prostate cancer (mCSPC) who achieve deep prostate-specific antigen (PSA) response may have improved survival. This finding may have implications for developing treatment de-escalation strategies. Thus, we assessed the overall survival by deep PSA response in mCSPC patients receiving intensified treatments. Methods: MEDLINE and EMBASE were systematically searched from each database’s inception through 1 st October 2022. Trials assessing androgen deprivation therapy intensification (doublets, triplets) and reporting overall survival (OS) by deep PSA response were considered eligible for inclusion. Deep PSA response was defined as the PSA level of less than 0.1 or 0.2 ng/ml within eight months after initiation of intensified treatment. Precomputed effect estimates of OS (deep PSA response vs no deep PSA response) were pooled using an inverse-variance approach after logarithmic transformation; a random-effects meta-analysis was conducted within the Bayesian framework using empirical informative priors for heterogeneity parameter as specified by Turner et al. Summary effect was expressed as hazard ratios (HR) with the corresponding 95% credible intervals (CrI). A sensitivity analysis was conducted using the Der Simonian-Lairds random-effects meta-analysis with Hartung-Knapp (HK) adjustment. Results: Five RCTs (PEACE-1, ARASENS, CHAARTED, LATITUDE, TITAN) with 2533 patients were included in this systematic review. A total of 1335 patients experienced a deep PSA response, while 1218 did not achieve a deep PSA response after the initiation of intensified treatment. The pooled incidence of deep PSA response was 49.45% (95% confidence interval: 37.75-61.18). Bayesian meta-analysis showed significantly improved OS in overall mCSPC patient population who achieved a deep PSA response after intensified treatment with either triplet or doublet therapy as compared to those who did not achieve a deep PSA response (HR: 0.39; 95% CI: 0.30-0.50) as shown. The results were consistent with HK adjustment. Conclusions: Excellent overall survival in patients with deep PSA response may offer an opportunity to guide treatment de-escalation trials in carefully selected mCSPC patients. [Table: see text]
Early outcomes from lutetium Lu-177 vipivotide tetraxetan treatment in patients selected for therapy with piflufolastat F-18 PET imaging.
Authors: Thomas Pence Boike, Vincent A. DiPippo, Heather Austin, Wendy Turnquist, Yusuf Qamruzzaman
Journal: Journal of Clinical Oncology (2023)

191 Background: The Vision trial utilized Ga 68 PSMA 11 imaging to select patients for treatment with Lutetium Lu 177 Vipivotide Tetraxetan. Current guidelines allow not only Ga 68 PSMA 11 PET but also Piflufolastat F 18 PET when selecting patients for Lutetium Lu 177 Vipivotide Tetraxetan but little is published on outcomes to this approach. Methods: Patients were enrolled on an IRB approved managed access protocol and were treated by a single investigator at a single institution. Eligible patients had mCRPC and had received previous treatment with at least one androgen receptor pathway inhibitor and at least one round of taxane based chemotherapy. Baseline imaging, demographics, treatment history, and tumor characteristics were collected. Patients were treated with 7.4 GBq of Lutetium Lu 177 Vipivotide Tetraxetan every 6 weeks for up to six cycles. Adverse events and PSA response were collected. Results: Fourteen patients were enrolled between August 2021 and August 2022. All patients had advanced mCRPC, were heavily pre-treated, and had failed both hormonal as well as chemotherapeutic options. The average number of androgen receptor pathway inhibitor courses for the cohort is 2.4 (range 1-4) and the average number of taxane courses for the cohort is 1.5 (Range 1-3). 11 patients underwent Piflufolastat F 18 PET and 3 patients had Ga 68 PSMA 11 PET. Baseline PSA varied significantly from 2.51 - 961.71 ng/mL. Declines of 50% in PSA were observed in 8/14 patients. 2 patients had greater than 80% PSA reductions. Conclusions: PSA treatment responses were similar to those reported in the Vision trial in this cohort of patients selected with either Piflufolastat F 18 PET or Ga 68 PSMA 11 PET supporting the guideline recommendations. Clinical trial information: NCT04825652 .
Cell-free urinary tumor DNA to detect minimal residual disease prior to repeat-transurethral resection of bladder tumor in non–muscle-invasive bladder cancer: A prospective study.
Authors: Kyle M. Rose, Prithvi Murthy, Billie Gould, Heather L Huelster, Facundo Davaro, Pan Du, Shidong Jia, Roger Li
Journal: Journal of Clinical Oncology (2023)

LBA445 Background: Cell-free urinary tumor DNA (utDNA) generated from tumor genomic sequencing is an emerging biomarker showing tremendous potential for detecting minimal residual disease (MRD) in muscle-invasive and metastatic bladder cancer. We performed a prospective study to assess utDNA’s ability to measure MRD at the time of standard-of-care repeat transurethral resection of bladder tumor (rTURBT) in non-muscle invasive bladder cancer (NMIBC). Methods: Patients with high-risk NMIBC were enrolled prior to rTURBT. Index tumor and rTURBT mutational profile was performed via PredicineWES whole exome sequencing across 20,000 genes. Genes with non-synonymous (NS) mutations observed in index and rTURBT specimens identified in a minimum of two samples are reported. Urine samples were taken immediately prior to r-TURBT. utDNA detection was performed by ultra-deep sequencing of urinary cfDNA using a custom panel of up to 50-baseline mutations per patient together with a fixed core panel covering hotspot regions and actionable variants via PredicineBEACON. Urinary tumor fraction was used to call utDNA positivity. The primary endpoint was the detection of utDNA to predict MRD at the time of repeat-TURBT. Results: Eleven patients underwent rTURBT for high-risk NMIBC. Residual tumor was detected at rTURBT in 8/11 (73%) patients. Fifty genes with NS mutations found in at least two samples were identified including TP53, PIK3CA, RB1, MYC, CDKN1A and ARID1A. A median of 146 (range 39-418) and 91 NS (range 2-312) mutations were identified in the index and re-TUR specimens, respectively. Concordance rates were 83% on average between index and rTURBT, highest for patients upstaged to T2 disease, and lowest for patients harboring CIS. New somatic variants not observed in the index tissue were detected in rTURBT for 4/6 patients and 7/14 were also detected in the pre-operative urine. Overall, 50% of utDNA mutations were concordant with index tumor tissue, 39% were concordant with rTURBT tissue, and 33% were concordant with both. The tumor fraction of utDNA was higher in patients with residual disease (mean 2.5% vs. 0.2%, p=0.10). Using tumor-fraction to predict MRD, the area under the receiver-operator curve was 0.85. Using an optimal threshold of ≥3.3% tumor-fraction to define utDNA positivity, the test had a sensitivity of 75% at 100% specificity. Conclusions: Urinary tumor DNA shows promise as a surrogate for minimal residual disease and may predict TURBT pathology for NMIBC. Genomic alterations between index and rTURBT tumors are highly concordant in papillary tumors even in the setting of upstaging, which may aid in targeted intravesical or systemic therapy selection. Larger cohorts and long-term follow up is needed to determine if utDNA can risk-stratify patients prior to rTURBT and predict long-term recurrence.